Andrea Ciaranello

Effectiveness of pediatric antiretroviral therapy in resource-limited settings: a systematic review and meta-analysis.

BACKGROUND Responses to antiretroviral therapy (ART) among human immunodeficiency virus (HIV)-infected children in resource-limited settings have recently been reported, but outcomes vary. We sought to derive pooled estimates of the 12-month rate of virologic suppression (HIV RNA, <400 copies/mL) and gain in CD4 cell percentage (DeltaCD4%) for children initiating ART in resource-limited settings. METHODS We conducted a systematic review and meta-analysis of published reports of HIV RNA and CD4 outcomes for treatment-naive children aged 0-17 years old by means of the Medline, EMBASE (Excerpta Medica Database), and LILACS (Latin American and Caribbean Health Sciences Literature) electronic databases and the Cochrane Clinical Trials Register. Pooled estimates of the reported proportion with HIV RNA <400 copies/mL and DeltaCD4% after 12 months of ART were derived using patient-level estimates and fixed- and random-effects models. To approximate intention-to-treat analyses, in sensitivity analyses children with missing 12-month data were assumed to have HIV RNA>400 copies/mL or DeltaCD4% of zero. RESULTS In patient-level estimates after 12 months of ART, the pooled proportion with virologic suppression was 70% (95% confidence interval [CI], 67%-73%); the pooled DeltaCD4% was 13.7% (95% CI, 11.8%-15.7%). Results from the fixed- and random-effects models were similar. In approximated intention-to-treat analyses, the pooled estimates decreased to 53% with virologic suppression (95% CI, 50%-55%) and to a DeltaCD4% of 8.5% (95% CI, 5.5%-11.4%). CONCLUSIONS Pooled estimates of reported virologic and immunologic benefits after 12 months of ART among HIV-infected children in resource-limited settings are comparable with those observed among children in developed settings. Consistency in reporting on reasons for missing data will aid in the evaluation of ART outcomes in resource-limited settings.

Scaling up the 2010 World Health Organization HIV Treatment Guidelines in resource-limited settings: a model-based analysis.

Rochelle Walensky and colleagues use a model-based analysis to examine which of the 2010 WHO antiretroviral therapy guidelines should be implemented first in resource-limited settings by ranking them according to survival, cost-effectiveness, and equity.

Sustainable HIV treatment in Africa through viral-load-informed differentiated care

There are inefficiencies in current approaches to monitoring patients on antiretroviral therapy in sub-Saharan Africa. Patients typically attend clinics every 1 to 3 months for clinical assessment. The clinic costs are comparable with the costs of the drugs themselves and CD4 counts are measured every 6 months, but patients are rarely switched to second-line therapies. To ensure sustainability of treatment programmes, a transition to more cost-effective delivery of antiretroviral therapy is needed. In contrast to the CD4 count, measurement of the level of HIV RNA in plasma (the viral load) provides a direct measure of the current treatment effect. Viral-load-informed differentiated care is a means of tailoring care so that those with suppressed viral load visit the clinic less frequently and attention is focussed on those with unsuppressed viral load to promote adherence and timely switching to a second-line regimen. The most feasible approach to measuring viral load in many countries is to collect dried blood spot samples for testing in regional laboratories; however, there have been concerns over the sensitivity and specificity of this approach to define treatment failure and the delay in returning results to the clinic. We use modelling to synthesize evidence and evaluate the cost-effectiveness of viral-load-informed differentiated care, accounting for limitations of dried blood sample testing. We find that viral-load-informed differentiated care using dried blood sample testing is cost-effective and is a recommended strategy for patient monitoring, although further empirical evidence as the approach is rolled out would be of value. We also explore the potential benefits of point-of-care viral load tests that may become available in the future.This article has not been written or reviewed by Nature editors. Nature accepts no responsibility for the accuracy of the information provided.

What Will It Take to Eliminate Pediatric HIV? Reaching WHO Target Rates of Mother-to-Child HIV Transmission in Zimbabwe: A Model-Based Analysis

Using a simulation model, Andrea Ciaranello and colleagues find that the latest WHO PMTCT (prevention of mother to child transmission of HIV) guidelines plus better access to PMTCT programs, better retention of women in care, and better adherence to drugs are needed to eliminate pediatric HIV in Zimbabwe.

Cost-effectiveness of World Health Organization 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe

We projected outcomes for mothers and infants following World Health Organization–recommended regimens to prevent mother-to-child human immunodeficiency virus (HIV) transmission. Compared with Option A, Option B improves life expectancy and saves money; compared with Option B, lifelong maternal therapy is of comparable value to common HIV-related interventions.

WHO 2010 Guidelines for Prevention of Mother-to-Child HIV Transmission in Zimbabwe: Modeling Clinical Outcomes in Infants and Mothers

Background The Zimbabwean national prevention of mother-to-child HIV transmission (PMTCT) program provided primarily single-dose nevirapine (sdNVP) from 2002–2009 and is currently replacing sdNVP with more effective antiretroviral (ARV) regimens. Methods Published HIV and PMTCT models, with local trial and programmatic data, were used to simulate a cohort of HIV-infected, pregnant/breastfeeding women in Zimbabwe (mean age 24.0 years, mean CD4 451 cells/µL). We compared five PMTCT regimens at a fixed level of PMTCT medication uptake: 1) no antenatal ARVs (comparator); 2) sdNVP; 3) WHO 2010 guidelines using “Option A” (zidovudine during pregnancy/infant NVP during breastfeeding for women without advanced HIV disease; lifelong 3-drug antiretroviral therapy (ART) for women with advanced disease); 4) WHO “Option B” (ART during pregnancy/breastfeeding without advanced disease; lifelong ART with advanced disease); and 5) “Option B+:” lifelong ART for all pregnant/breastfeeding, HIV-infected women. Pediatric (4–6 week and 18-month infection risk, 2-year survival) and maternal (2- and 5-year survival, life expectancy from delivery) outcomes were projected. Results Eighteen-month pediatric infection risks ranged from 25.8% (no antenatal ARVs) to 10.9% (Options B/B+). Although maternal short-term outcomes (2- and 5-year survival) varied only slightly by regimen, maternal life expectancy was reduced after receipt of sdNVP (13.8 years) or Option B (13.9 years) compared to no antenatal ARVs (14.0 years), Option A (14.0 years), or Option B+ (14.5 years). Conclusions Replacement of sdNVP with currently recommended regimens for PMTCT (WHO Options A, B, or B+) is necessary to reduce infant HIV infection risk in Zimbabwe. The planned transition to Option A may also improve both pediatric and maternal outcomes.

Cost-effectiveness of different strategies to monitor adults on antiretroviral treatment: a combined analysis of three mathematical models

BACKGROUND WHOs 2013 revisions to its Consolidated Guidelines on antiretroviral drugs recommend routine viral load monitoring, rather than clinical or immunological monitoring, as the preferred monitoring approach on the basis of clinical evidence. However, HIV programmes in resource-limited settings require guidance on the most cost-effective use of resources in view of other competing priorities such as expansion of antiretroviral therapy coverage. We assessed the cost-effectiveness of alternative patient monitoring strategies. METHODS We evaluated a range of monitoring strategies, including clinical, CD4 cell count, and viral load monitoring, alone and together, at different frequencies and with different criteria for switching to second-line therapies. We used three independently constructed and validated models simultaneously. We estimated costs on the basis of resource use projected in the models and associated unit costs; we quantified impact as disability-adjusted life years (DALYs) averted. We compared alternatives using incremental cost-effectiveness analysis. FINDINGS All models show that clinical monitoring delivers significant benefit compared with a hypothetical baseline scenario with no monitoring or switching. Regular CD4 cell count monitoring confers a benefit over clinical monitoring alone, at an incremental cost that makes it affordable in more settings than viral load monitoring, which is currently more expensive. Viral load monitoring without CD4 cell count every 6-12 months provides the greatest reductions in morbidity and mortality, but incurs a high cost per DALY averted, resulting in lost opportunities to generate health gains if implemented instead of increasing antiretroviral therapy coverage or expanding antiretroviral therapy eligibility. INTERPRETATION The priority for HIV programmes should be to expand antiretroviral therapy coverage, firstly at CD4 cell count lower than 350 cells per μL, and then at a CD4 cell count lower than 500 cells per μL, using lower-cost clinical or CD4 monitoring. At current costs, viral load monitoring should be considered only after high antiretroviral therapy coverage has been achieved. Point-of-care technologies and other factors reducing costs might make viral load monitoring more affordable in future. FUNDING Bill & Melinda Gates Foundation, WHO.

Cost-Effectiveness of Laboratory Monitoring in Sub-Saharan Africa: A Review of the Current Literature

As the global community evaluates the unprecedented investment in the scale-up of human immunodeficiency virus (HIV) therapy and considers future investments in HIV care, it is crucial to identify those HIV interventions that maximize the benefit realized from each dollar spent. The use of laboratory monitoring assays--CD4 cell count and HIV RNA level--in decisions about when to initiate and switch antiretroviral therapy may offer substantial clinical benefit, but their economic value remains controversial. Cost-effectiveness analysis can be used to evaluate the value for money of strategies for HIV care, including alternative approaches to laboratory monitoring. Five published cost-effectiveness analyses address the question of CD4 cell count and HIV RNA level monitoring for HIV-infected patients in Africa, with differing conclusions. We describe the use of cost-effectiveness analysis in resource-limited settings and review the cost-effectiveness literature with regard to monitoring the CD4 cell count and HIV RNA level in Africa, highlighting some of the most critical issues in this debate.

First-line antiretroviral therapy after single-dose nevirapine exposure in South Africa: a cost-effectiveness analysis of the OCTANE trial

Background:The OCTANE trial reports superior outcomes of lopinavir/ritonavir vs. nevirapine-based antiretroviral therapy (ART) among women previously exposed to single-dose nevirapine to prevent mother-to-child HIV transmission. However, lopinavir/ritonavir is 12 times costlier than nevirapine. Methods:We used a computer model, with OCTANE and local data, to simulate HIV-infected, single-dose nevirapine-exposed women in South Africa. Outcomes of three alternative ART sequences were projected: no ART (for comparison), first-line nevirapine, and first-line lopinavir/ritonavir. OCTANE data included mean age (31 years) and CD4 cell count (135/μl); median time since single-dose nevirapine (17 months); and 24-week viral suppression efficacy for first-line ART (nevirapine: 85%, lopinavir/ritonavir: 97%). Outcomes included life expectancy, per-person costs (2008 US

Antiretroviral drugs for preventing mother-to-child transmission of HIV in sub-Saharan Africa: Balancing efficacy and infant toxicity

), and incremental cost-effectiveness ratios. Results:With no ART, projected life expectancy was 1.6 years and per-person cost was